Adipocyte Dynamics and Reversible Metabolic Syndrome in Mice with an Inducible Adipocyte-Specific Deletion of the Insulin Receptor

Abstract

Insulin and IGF1 signaling are important for adipose tissue development and function; however, their role in mature adipocytes is unclear. Mice with atamoxifen-inducible knockout of insulin and/or IGF1 receptors (IR/IGF1R) demonstrate a rapid loss of white and brown fat due to increased lipolysis and adipocyte apoptosis. This results in insulin resistance, glucose intolerance, hepatosteatosis, islet hyperplasia with hyperinsulinemia, and cold intolerance. This phenotype, however, resolves over 10-30days due to a proliferation of preadipocytes and rapid regeneration of both brown and white adipocytes as identified by mTmG lineage tracing. This cycle can be repeated with a second round of receptor inactivation. Leptin administration prior to tamoxifen treatment blocks development of the metabolic syndrome without affecting adipocyte loss or regeneration. Thus, IRis critical in adipocyte maintenance, and this loss of adipose tissue stimulates regeneration of brown/white fat and reversal of metabolic syndrome associated with fat loss.